Dry powder inhaler

ABSTRACT

This invention provides a dry powder inhaler comprising: a dry powder medicament comprising fluticasone propionate, salmeterol xinafoate and a lactose carrier; wherein, the delivered dose of salmeterol per actuation is less than 50 μg; and wherein the dose provides a baseline-adjusted FEV 1  in a patient of more than 150 mL within 30 minutes of receiving the dose. A method of treating a patient includes administering to a patient a dry powder medicament having fluticasone propionate, salmeterol xinafoate and a lactose carrier; wherein, the delivered dose of salmeterol per actuation is less than 50 μg; and wherein the dose provides a baseline-adjusted FEV 1  in a patient of more than 150 mL within 30 minutes of receiving the dose.

This application claims priority from U.S. Provisional Application No.61/887,589, filed Oct. 7, 2013, and from U.S. Provisional ApplicationNo. 61/888,301, filed Oct. 8, 2013. The disclosures of each of theseapplications are incorporated herein by reference in their entirety forall purposes.

The present invention relates to a dry powder inhaler, and particularlyto a dry powder inhaler containing a combination of fluticasone andsalmeterol.

Fluticasone propionate is a corticosteroid indicated for the treatmentof asthma and allergic rhinitis. It is also used to treat eosinophilicesophagitis. It is named asS-(fluoromethyl)-6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate-17-propanoateand has the following structure:

Salmeterol is a long-acting β₂-adrenergic receptor agonist that isindicated for the treatment of asthma and chronic obstructive pulmonarydisease (COPD). It is named as(RS)-2-(hydroxymethyl)-4-{1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl}phenol and has the following structure:

Salmeterol is typically administered as the xinafoate salt, thestructure of which is well-known in the art.

The combination of salmeterol (as the xinafoate salt) and fluticasonepropionate is marketed in the EU by Allen & Hanburys as Seretide®, usingeither the Evohaler® pressurised metered-dose inhaler (pMDI) or theAccuhaler® dry powder inhaler (DPI). The Accuhaler® uses blisters filledwith a blend of the micronised active agents and lactose monohydrate. Itis marketed in three dosage strengths, each providing 50 micrograms ofsalmeterol xinafoate and 100, 250 or 500 micrograms of fluticasonepropionate. The delivered doses are lower. In the US, the product iscalled Advair® and the inhaler is called Diskus®.

Seretide is indicated in the regular treatment of asthma where use of acombination product (long-acting β₂-agonist and inhaled corticosteroid)is appropriate. This is where either: patients are not adequatelycontrolled with inhaled corticosteroids and as needed inhaled shortacting β₂-agonist; or patients are already adequately controlled on bothinhaled corticosteroid and long-acting β₂-agonist.

Seretide is also indicated for the symptomatic treatment of patientswith COPD, with a FEV₁<60% predicted normal (pre-bronchodilator) and ahistory of repeated exacerbations, who have significant symptoms despiteregular bronchodilator therapy. FEV₁ is a measurement used in spirometrywhich means the forced expiratory volume in one second. This is theamount of air which can be forcibly exhaled from the lungs in the firstsecond of a forced exhalation. The measurement of FEV₁ is used byhealthcare professionals to determine lung function.

Combination products are well established in the art and are known toimprove patient convenience and compliance. A drawback of combinationproducts are that control over the dose of the individual activeingredients is reduced. For the inhaled corticosteroid, this is not aserious concern because the therapeutic window of inhaledcorticosteroids is wide. That is, it is difficult for a patient toexceed the recommended daily intake of inhaled corticosteroid. However,the β₂-agonist is more of a concern since the therapeutic window isnarrower and β₂-agonists are associated with serious adverse effects,including cardiac side-effects.

Thus, there is a requirement in the art for an improvedfluticasone/salmeterol combination product which retains the therapeuticeffect of both products, but which reduces the adverse effectsassociated with the salmeterol.

Accordingly, the present invention provides a dry powder inhalercomprising: a dry powder medicament comprising fluticasone propionate,salmeterol xinafoate and a lactose carrier; wherein, the delivered doseof salmeterol per actuation is less than 50 μg; and wherein the doseprovides a baseline-adjusted FEV₁ in a patient of more than 150 mLwithin 30 minutes of receiving the dose.

The present invention also provides a method for the treatment ofasthma, allergic rhinitis, or COPD comprising administering to a patienta dry powder medicament according to any embodiment described herein. Inone embodiment, the dry powder medicament comprises fluticasonepropionate, salmeterol xinafoate and a lactose carrier; wherein, thedelivered dose of salmeterol per actuation is less than 50 μg; andwherein the dose provides a baseline-adjusted FEV₁ in a patient of morethan 150 mL within 30 minutes of receiving the dose. The method oftreatment may use any inhaler, including any inhaler as describedherein. In one embodiment, the method of treatment provides a dose ofsalmeterol that is less than 25 μg. In other embodiments, the method oftreatment provides doses of fluticasone/salmeterol in μg that are500/12.5, 400/12.5, 250/12.5, 200/12.5, 100/12.5, 50/12.5 or 25/12.5 peractuation.

The present invention also provides a method of measuring a delivereddose of active agent by an inhaler comprising:inserting the inhaler intoa mouthpiece adapter; actuating the inhaler to provide a delivered dosethrough the mouthpiece adapter and into a dosage unit samplingapparatus; rinsing the mouthpiece adapter with a solvent and into thedosage unit sampling apparatus; dissolving the delivered dose in thedosage unit sampling apparatus; filtering the dissolved delivered doseto provide a filtered solution; and analyzing the filtered solution todetermine the amount of the active agent in the delivered dose. Themethod of measuring may be carried out at the beginning, the middle andthe end of the life of the inhaler.

Several types of dry powder inhaler are known in the art. In a preferredembodiment of the present invention, the dry powder inhaler comprisesthe following features.

The preferred inhaler includes a delivery passageway for directing aninhalation-induced air flow through a mouthpiece, a channel extendingfrom the delivery passageway to the medicament, and more preferably amouthpiece for patient inhalation, a delivery passageway for directingan inhalation-induced air flow through the mouthpiece, a channelextending from the delivery passageway, and a reservoir for containingmedicament, with the reservoir having a dispenser port connected to thechannel. In a preferred form, the dose metering system includes a cupreceived in the channel, which is movable between the dispenser port andthe delivery passageway, a cup spring biasing the cup towards one of thedispenser port and the passageway, and a yoke movable between at leasttwo positions. The yoke includes a ratchet engaging the cup andpreventing movement of the cup when the yoke is in one of the positions,and allowing movement of the cup when the yoke is in another of thepositions.

The inhaler preferably includes a cyclone deagglomerator for breaking upagglomerates of the active ingredients and carrier. This occurs prior toinhalation of the powder by a patient. The deagglomerator includes aninner wall defining a swirl chamber extending along an axis from a firstend to a second end, a dry powder supply port, an inlet port, and anoutlet port.

The supply port is in the first end of the swirl chamber for providingfluid communication between a dry powder delivery passageway of theinhaler and the first end of the swirl chamber. The inlet port is in theinner wall of the swirl chamber adjacent to the first end of the swirlchamber and provides fluid communication between a region exterior tothe deagglomerator and the swirl chamber. The outlet port provides fluidcommunication between the second end of the swirl chamber and a regionexterior to the deagglomerator.

A breath induced low pressure at the outlet port causes air flows intothe swirl chamber through the dry powder supply port and the inlet port.The air flows collide with each other and with the wall of the swirlchamber prior to exiting through the outlet port, such that the activeis detached from the carrier (lactose). The deagglomerator furtherincludes vanes at the first end of the swirl chamber for creatingadditional collisions and impacts of entrained powder.

A first breath-actuated air flow is directed for entraining a dry powderfrom an inhaler into a first end of a chamber extending longitudinallybetween the first end and a second end, the first air flow directed in alongitudinal direction.

A second breath-actuated airflow is directed in a substantiallytransverse direction into the first end of the chamber such that the airflows collide and substantially combine.

Then, a portion of the combined air flows is deflected in asubstantially longitudinal direction towards a second end of thechamber, and a remaining portion of the combined air flows is directedin a spiral path towards the second end of the chamber. All the combinedair flows and any dry powder entrained therein are then delivered fromthe second end of the chamber to a patient's mouth.

The deagglomerator ensures that particles of the actives are smallenough for adequate penetration of the powder into a bronchial region ofa patient's lungs during inhalation by the patient.

Thus, in an embodiment of the present invention, the deagglomeratorcomprises: an inner wall defining a swirl chamber extending along anaxis from a first end to a second end; a dry powder supply port in thefirst end of the swirl chamber for providing fluid communication betweena dry powder delivery passageway of the inhaler and the first end of theswirl chamber; at least one inlet port in the inner wall of the swirlchamber adjacent to the first end of the swirl chamber providing fluidcommunication between a region exterior to the deagglomerator and thefirst end of the swirl chamber; an outlet port providing fluidcommunication between the second end of the swirl chamber and a regionexterior to the deagglomerator; and vanes at the first end of the swirlchamber extending at least in part radially outwardly from the axis ofthe chamber, each of the vanes having an oblique surface facing at leastin part in a direction transverse to the axis; whereby a breath inducedlow pressure at the outlet port causes air flows into the swirl chamberthrough the dry powder supply port and the inlet port.

The inhaler preferably has a reservoir for containing the medicament andan arrangement for delivering a metered dose of the medicament from thereservoir. The reservoir is typically a pressure system. The inhalerpreferably includes: a sealed reservoir including a dispensing port; achannel communicating with the dispensing port and including a pressurerelief port; a conduit providing fluid communication between an interiorof the sealed reservoir and the pressure relief port of the channel; anda cup assembly movably received in the channel and including, a recessadapted to receive medicament when aligned with the dispensing port, afirst sealing surface adapted to seal the dispensing port when therecess is unaligned with the dispensing port, and a second sealingsurface adapted to sealing the pressure relief port when the recess isaligned with the dispensing port and unseal the pressure relief portwhen the recess is unaligned with the dispensing port.

The inhaler preferably has a dose counter. The inhaler includes amouthpiece for patient inhalation, a dose-metering arrangement includinga pawl movable along a predetermined path during the metering of a doseof medicament to the mouthpiece by the dose-metering arrangement, and adose counter.

In a preferred form, the dose counter includes a bobbin, a rotatablespool, and a rolled ribbon received on the bobbin, rotatable about anaxis of the bobbin. The ribbon has indicia thereon successivelyextending between a first end of the ribbon secured to the spool and asecond end of the ribbon positioned on the bobbin. The dose counter alsoincludes teeth extending radially outwardly from the spool into thepredetermined path of the pawl so that the spool is rotated by the pawland the ribbon advanced onto the spool during the metering of a dose tothe mouthpiece.

The preferred inhaler includes a simple, accurate and consistentmechanical dose metering system that dispenses dry powdered medicamentin discrete amounts or doses for patient inhalation, a reservoirpressure system that ensures consistently dispensed doses, and a dosecounter indicating the number of doses remaining in the inhaler.

The present invention will now be described with reference to thedrawings, in which:

FIG. 1 is a first side isometric view of a dry powder inhaler accordingto a preferred embodiment;

FIG. 2 is an exploded, second side isometric view of the inhaler of FIG.1;

FIG. 3 is a second side isometric view of a main assembly of the inhalerof FIG. 1;

FIG. 4 is a second side isometric view of the main assembly of theinhaler of FIG. 1, shown with a yoke removed;

FIG. 5 is an exploded first side isometric view of the main assembly ofthe inhaler of FIG. 1;

FIG. 6 is an exploded enlarged isometric view of a medicament cup of theinhaler of FIG. 1;

FIG. 7 is an exploded first side isometric view of a hopper and adeagglomerator of the inhaler of FIG. 1;

FIG. 8 is an exploded second side isometric view of the hopper and aswirl chamber roof of the deagglomerator of the inhaler of FIG. 1;

FIG. 9 is an exploded first side isometric view of a case, cams and amouthpiece cover of the inhaler of FIG. 1;

FIG. 10 is an enlarged side isometric view of one of the cams of theinhaler of FIG. 1;

FIG. 11 is a second side isometric view of the yoke of the inhaler ofFIG. 1;

FIG. 12 is a first side isometric view of the yoke of the inhaler ofFIG. 1, showing a ratchet and a push bar of the yoke;

FIG. 13 is a schematic illustration of lateral movement of a boss of themedicament cup in response to longitudinal movement of the ratchet andthe push bar of the yoke of the inhaler of FIG. 1;

FIG. 14 is an enlarged isometric view of a dose counter of the inhalerof FIG. 1;

FIG. 15 is an exploded enlarged isometric view of the dose counter ofthe inhaler of FIG. 1; and

FIG. 16 is an enlarged isometric view, partially in section, of aportion of the inhaler of FIG. 1 illustrating medicament inhalationthrough the inhaler.

FIG. 17 is an exploded isometric view of a deagglomerator according tothe present disclosure;

FIG. 18 is a side elevation view of the deagglomerator of FIG. 17;

FIG. 19 is a top plan view of the deagglomerator of FIG. 17;

FIG. 20 is a bottom plan view of the deagglomerator of FIG. 17;

FIG. 21 is a sectional view of the deagglomerator of FIG. 17 taken alongline 5′-5′ of FIG. 18;

FIG. 22 is a sectional view of the deagglomerator of FIG. 17 taken alongline 6′-6′ of FIG. 19; and

FIG. 23 shows a comparison between FS Spiromax® (invention) and FSAdvair® (comparison).

The inhaler 10 generally includes a housing 18, and an assembly 12received in the housing (see FIG. 2). The housing 18 includes a case 20having an open end 22 and a mouthpiece 24 for patient inhalation, a cap26 secured to and closing the open end 22 of the case 20, and a cover 28pivotally mounted to the case 20 for covering the mouthpiece 24 (seeFIGS. 1, 2 and 9). The housing 18 is preferably manufactured from aplastic such as polypropylene, acetal or moulded polystyrene, but may bemanufactured from metal or another suitable material.

The internal assembly 12 includes a reservoir 14 for containing drypowered medicament in bulk form, a deagglomerator 10′ that breaks downthe medicament between a delivery passageway 34 and the mouthpiece 24,and a spacer 38 connecting the reservoir to the deagglomerator.

The reservoir 14 is generally made up of a collapsible bellows 40 and ahopper 42 having an dispenser port 44 (see FIGS. 2-5 and 7-8) fordispensing medicament upon the bellows 40 being at least partiallycollapsed to reduce the internal volume of the reservoir.

The hopper 42 is for holding the dry powder medicament in bulk form andhas an open end 46 closed by the flexible accordion-like bellows 40 in asubstantially air-tight manner.

An air filter 48 covers the open end 46 of the hopper 42 and preventsdry powder medicament from leaking from the hopper 42 (see FIG. 7).

A base 50 of the hopper 42 is secured to a spacer 38, which is in turnsecured to the deagglomerator 10′ (see FIGS. 3-5 and 7-8). The hopper42, the spacer 38, and the deagglomerator 10′ are preferablymanufactured from a plastic such as polypropylene, acetal or mouldedpolystyrene, but may be manufactured from metal or another suitablematerial.

The hopper 42, the spacer 38 and the deagglomerator 10′ are connected ina manner that provides an air tight seal between the parts. For thispurpose heat or cold sealing, laser welding or ultrasonic welding couldbe used, for example.

The spacer 38 and the hopper 42 together define the medicament deliverypassageway 34, which preferably includes a venturi 36 (see FIG. 16) forcreating an entraining air flow. The spacer 38 defines a slide channel52 communicating with the dispenser port 44 of the hopper 42, and achimney. 54 providing fluid communication between the medicamentdelivery passageway 34 and a supply port 22′ of the deagglomerator 10′(see FIGS. 7 and 8). The slide channel 52 extends generally normal withrespect to the axis “A” of the inhaler 10.

The deagglomerator 10′ breaks down agglomerates of dry powder medicamentbefore the dry powder leaves the inhaler 10 through the mouthpiece 24.

Referring to FIGS. 17 to 22, the deagglomerator 10′ breaks downagglomerates of medicament, or medicament and carrier, before inhalationof the medicament by a patient. In general, the deagglomerator 10′includes an inner wall 12′ defining a swirl chamber 14′ extending alongan axis A′ from a first end 18′ to a second end 20′. The swirl chamber14′ includes circular cross-sectional areas arranged transverse to theaxis A′, that decrease from the first end 18′ to the second end 20′ ofthe swirl chamber 14′, such that any air flow traveling from the firstend of the swirl chamber to the second end will be constricted and atleast in part collide with the inner wall 12′ of the chamber.

Preferably, the cross-sectional areas of the swirl chamber 14′ decreasemonotonically. In addition, the inner wall 12′ is preferably convex,i.e., arches inwardly towards the axis A′, as shown best in FIG. 22.

As shown in FIGS. 17, 19 and 22, the deagglomerator 10′ also includes adry powder supply port 22′ in the first end 18′ of the swirl chamber 14′for providing fluid communication between a dry powder deliverypassageway of an inhaler and the first end 18′ of the swirl chamber 14′.Preferably, the dry powder supply port 22′ faces in a directionsubstantially parallel with the axis A′ such that an air flow,illustrated by arrow 1′ in FIG. 22, entering the chamber 14′ through thesupply port 22′ is at least initially directed parallel with respect tothe axis A′ of the chamber.

Referring to FIGS. 17 to 22, the deagglomerator 10′ additionallyincludes at least one inlet port 24′ in the inner wall 12′ of the swirlchamber 14′ adjacent to or near the first end 18′ of the chamberproviding fluid communication between a region exterior to thedeagglomerator and the first end 18′ of the swirl chamber 14′.Preferably, the at least one inlet port comprises two diametricallyopposed inlet ports 24′, 25′ that extend in a direction substantiallytransverse to the axis A′ and substantially tangential to the circularcross-section of the swirl chamber 14′. As a result, air flows,illustrated by arrows 2′ and 3′ in FIGS. 17 and 21, entering the chamber14′ through the inlet ports are at least initially directed transversewith respect to the axis A′ of the chamber and collide with the air flow1′ entering through the supply port 22′ to create turbulence. Thecombined air flows, illustrated by arrow 4′ in FIGS. 21 and 22, thencollide with the inner wall 12′ of the chamber 14′, form a vortex, andcreate additional turbulence as they move towards the second end 20′ ofthe chamber.

Referring to FIGS. 17-19 and 22, the deagglomerator 10′ includes vanes26′ at the first end 18′ of the swirl chamber 14′ extending at least inpart radially outwardly from the axis A′ of the chamber. Each of thevanes 26′ has an oblique surface 28′ facing at least in part in adirection transverse to the axis A′ of the chamber. The vanes 26′ aresized such that at least a portion 4A′ of the combined air flows 4′collide with the oblique surfaces 28′, as shown in FIG. 22. Preferably,the vanes comprise four vanes 26′, each extending between a hub 30′aligned with the axis A′ and the wall 12′ of the swirl chamber 14′.

As shown in FIGS. 17 to 22, the deagglomerator 10′ further includes anoutlet port 32′ providing fluid communication between the second end 20′of the swirl chamber 14′ and a region exterior to the deagglomerator. Abreath induced low pressure at the outlet port 32′ causes the air flow1′ through the supply port 22′ and the air flows 2′,3′ through the inletports and draws the combined air flow 4′ through the swirl chamber 14′.The combined air flow 4′ then exits the deagglomerator through theoutlet port 32′. Preferably the outlet port 32′ extends substantiallytransverse to the axis A′, such that the air flow 4′ will collide withan inner wall of the outlet port 32′ and create further turbulence.

During use of the deagglomerator 10′ in combination with the inhaler,patient inhalation at the outlet port 32′ causes air flows 1′,2′,3′ toenter through, respectively, the dry powder supply port 22′ and theinlet ports. Although not shown, the air flow 1′ through the supply port22′ entrains the dry powder into the swirl chamber 14′. The air flow 1′and entrained dry powder are directed by the supply port 22′ into thechamber in a longitudinal direction, while the air flows 2′,3′ from theinlet ports are directed in a transverse direction, such that the airflows collide and substantially combine.

A portion of the combined air flow 4′ and the entrained dry powder thencollide with the oblique surfaces 28′ of the vanes 26′ causing particlesand any agglomerates of the dry powder to impact against the obliquesurfaces and collide with each other. The geometry of the swirl chamber14′ causes the combined air flow 4′ and the entrained dry powder tofollow a turbulent, spiral path, or vortex, through the chamber. As willbe appreciated, the decreasing cross-sections of the swirl chamber 14′continuously changes the direction and increases the velocity of thespiralling combined air flow 4′ and entrained dry powder. Thus,particles and any agglomerates of the dry powder constantly impactagainst the wall 12′ of the swirl chamber 14′ and collide with eachother, resulting in a mutual grinding or shattering action between theparticles and agglomerates. In addition, particles and agglomeratesdeflected off the oblique surfaces 28′ of the vanes 26′ cause furtherimpacts and collisions.

Upon exiting the swirl chamber 14′, the direction of the combined airflow 4 and the entrained dry powder is again changed to a transversedirection with respect to the axis A′, through the outlet port 32′. Thecombined air flow 4′ and the entrained dry powder retain a swirlcomponent of the flow, such that the air flow 4′ and the entrained drypowder spirally swirls through the outlet port 32′. The swirling flowcauses additional impacts in the outlet port 32′ so as to result infurther breaking up of any remaining agglomerates prior to being inhaledby a patient.

As shown in FIGS. 17 to 22, the deagglomerator is preferably assemblyfrom two pieces: a cup-like base 40′ and a cover 42′. The base 40′ andthe cover 42′ are connected to form the swirl chamber 14′. The cup-likebase 40′ includes the wall 12′ and the second end 20′ of the chamber anddefines the outlet port 32′. The base 40′ also includes the inlet portsof the swirl chamber 14′. The cover 42′ forms the vanes 26′ and definesthe supply port 22′.

The base 40′ and the cover 42′ of the deagglomerator are preferablymanufactured from a plastic such as polypropylene, acetal or mouldedpolystyrene, but may be manufactured from metal or another suitablematerial. Preferably, the cover 42′ includes an anti-static additive, sothat dry powder will not cling to the vanes 26′. The base 40′ and thecover 42′ are then connected in a manner that provides an air tight sealbetween the parts. For this purpose heat or cold sealing, laser weldingor ultra-sonic welding could be used, for example.

Although the inhaler 10 is shown with a particular deagglomerator 10′,the inhaler 10 is not limited to use with the deagglomerator shown andcan be used with other types of deagglomerators or a simple swirlchamber.

The dose metering system includes a first yoke 66 and a second yoke 68mounted on the internal assembly 12 within the housing 18, and movablein a linear direction parallel with an axis “A” of the inhaler 10 (seeFIG. 2). An actuation spring 69 is positioned between the cap 26 of thehousing 18 and the first yoke 66 for biasing the yokes in a firstdirection towards the mouthpiece 24. In particular, the actuation spring69 biases the first yoke 66 against the bellows 40 and the second yoke68 against cams 70 mounted on the mouthpiece cover 28 (see FIG. 9).

The first yoke 66 includes an opening 72 that receives and retains acrown 74 of the bellows 40 such that the first yoke 66 pulls and expandsthe bellows 40 when moved towards the cap 26, i.e., against theactuation spring 69 (see FIG. 2). The second yoke 68 includes a belt 76,which receives the first yoke 66, and two cam followers 78 extendingfrom the belt in a direction opposite the first yoke 66 (see FIGS. 3, 11and 12), towards the cams 70 of the mouthpiece cover 28 (FIGS. 9,10).

The dose metering system also includes the two cams 70 mounted on themouthpiece cover 28 (see FIGS. 9 and 10), and movable with the cover 28between open and closed positions. The cams 70 each include an opening80 for allowing outwardly extending hinges 82 of the case 20 to passtherethrough and be received in first recesses 84 of the cover 28. Thecams 70 also include bosses 86 extending outwardly and received insecond recesses 88 of the cover 28, such that the cover 28 pivots aboutthe hinges 82 and the cams 70 move with the cover 28 about the hinges.

Each cam 70 also includes first, second and third cam surfaces 90,92,94,and the cam followers 78 of the second yoke 68 are biased against thecam surfaces by the actuation spring 69. The cam surfaces 90,92,94 arearranged such the cam followers 78 successively engage the first camsurfaces 90 when the cover 28 is closed, the second cam surfaces 92 whenthe cover 28 is partially opened, and the third cam surfaces 94 when thecover 28 is fully opened. The first cam surfaces 90 are spaced furtherfrom the hinges 82 than the second and the third cam surfaces, while thesecond cam surfaces 92 are spaced further from the hinges 82 than thethird cam surfaces 94. The cams 70, therefore, allow the yokes 66,68 tobe moved by the actuation spring 69 parallel with the axis “A” of theinhaler 10 in the first direction (towards the mouthpiece 24) throughfirst, second and third positions as the cover 28 is opened. The cams 70also push the yokes 66, 68 in a second direction parallel with the axis“A” (against the actuation spring 69 and towards the cap 26 of thehousing 18) through the third, the second and the first positions as thecover 28 is closed.

The dose metering system further includes a cup assembly 96 movablebetween the dispenser port 44 of the reservoir 14 and the deliverypassageway 34. The cup assembly 96 includes a medicament cup 98 mountedin a sled 100 slidably received in the slide channel 52 of the spacer 38below the hopper 42 (see FIGS. 5 and 6). The medicament cup 98 includesa recess 102 adapted to receive medicament from the dispenser port 44 ofthe reservoir 14 and sized to hold a predetermined dose of dry powderedmedicament when filled. The cup sled 100 is biased along the slidechannel 52 from the dispenser port 44 of the hopper 42 towards thedelivery passageway 34 by a cup spring 104, which is secured on thehopper 42 (see FIGS. 4 and 5).

The dose metering system also includes a ratchet 106 and a push bar 108on one of the cam followers 78 of the second yoke 68 that engage a boss110 of the cup sled 100 (see FIGS. 5,11 and 12). The ratchet 106 ismounted on a flexible flap 112 and is shaped to allow the boss 110 ofthe sled 100 to depress and pass over the ratchet 106, when the boss 110is engaged by the push bar 108. Operation of the dose metering system isdiscussed below.

The reservoir pressure system includes a pressure relief conduit 114 influid communication with the interior of the reservoir 14 (see FIGS. 7and 8), and a pressure relief port 116 in a wall of the slide channel 52(see FIGS. 5 and 8) providing fluid communication with the pressurerelief conduit 114 of the hopper 42.

The medicament cup assembly 96 includes a first sealing surface 118adapted to seal the dispenser port 44 upon the cup assembly being movedto the delivery passageway 34 (see FIGS. 5 and 6). A sealing spring 120is provided between the sled 100 and the cup 98 for biasing themedicament cup 98 against a bottom surface of the hopper 42 to seal thedispenser port 44 of the reservoir 14. The cup 98 includes clips 122that allow the cup to be biased against the reservoir, yet retain thecup in the sled 100.

The sled 100 includes a second sealing surface 124 adapted to seal thepressure relief port 116 when the recess 102 of the cup 98 is alignedwith the dispenser port 44, and an indentation 126 (see FIG. 6) adaptedto unseal the pressure relief port 116 when the first sealing surface118 is aligned with the dispenser port 44. Operation of the pressuresystem is discussed below.

The dose counting system 16 is mounted to the hopper 42 and includes aribbon 128, having successive numbers or other suitable indicia printedthereon, in alignment with a transparent window 130 provided in thehousing 18 (see FIG. 2). The dose counting system 16 includes arotatable bobbin 132, an indexing spool 134 rotatable in a singledirection, and the ribbon 128 rolled and received on the bobbin 132 andhaving a first end 127 secured to the spool 134, wherein the ribbon 128unrolls from the bobbin 132 so that the indicia is successivelydisplayed as the spool 134 is rotated or advanced.

The spool 134 is arranged to rotate upon movement of the yokes 66,68 toeffect delivery of a dose of medicament from the reservoir 14 into thedelivery passageway 34, such that the number on the ribbon 128 isadvanced to indicate that another dose has been dispensed by the inhaler10. The ribbon 128 can be arranged such that the numbers, or othersuitable indicia, increase or decrease upon rotation of the spool 134.For example, the ribbon 128 can be arranged such that the numbers, orother suitable indicia, decrease upon rotation of the spool 134 toindicate the number of doses remaining in the inhaler 10.

Alternatively, the ribbon 128 can be arranged such that the numbers, orother suitable indicia, increase upon rotation of the spool 134 toindicate the number of doses dispensed by the inhaler 10.

The indexing spool 134 preferably includes radially extending teeth 136,which are engaged by a pawl 138 extending from one of the cam followers78 (see FIGS. 3 and 11) of the second yoke 68 upon movement of the yoketo rotate, or advance, the indexing spool 134. More particularly, thepawl 138 is shaped and arranged such that it engages the teeth 136 andadvances the indexing spool 134 only upon the mouthpiece 24 cover 28being closed and the yokes 66,68 moved back towards the cap 26 of thehousing 18.

The dose counting system 16 also includes a chassis 140 that secures thedose counting system to the hopper 42 and includes shafts 142,144 forreceiving the bobbin 132 and the indexing spool 134. The bobbin shaft142 is preferably forked and includes radially nubs 146 for creating aresilient resistance to rotation of the bobbin 132 on the shaft 142. Aclutch spring 148 is received on the end of the indexing spool 134 andlocked to the chassis 140 to allow rotation of the spool 134 in only asingle direction (anticlockwise as shown in FIG. 14). Operation of thedose counting system 16 is discussed below.

FIG. 13 illustrates the relative movements of the boss 110 of the cupsled 100, and the ratchet 106 and the push bar 108 of the second yoke 68as the mouthpiece cover 28 is opened and closed. In the first positionof the yokes 66,68 (wherein the cover 28 is closed and the cam followers78 are in contact with the first cam surfaces 90 of the cams 70), theratchet 106 prevents the cup spring 104 from moving the cup sled 100 tothe delivery passageway 34. The dose metering system is arranged suchthat when the yokes are in the first position, the recess 102 of themedicament cup 98 is directly aligned with the dispenser port 44 of thereservoir 14 and the pressure relief port 116 of the spacer 38 is sealedby the second sealing surface 124 of the cup sled 100.

Upon the cover 28 being partially opened such that the second camsurfaces 92 of the cams 70 engage the cam followers 78, the actuatorspring 69 is allowed to move the yokes 66,68 linearly towards themouthpiece 24 to the second position and partially collapse the bellows40 of the medicament reservoir 14. The partially collapsed bellows 40pressurizes the interior of the reservoir 14 and ensures medicamentdispensed from the dispenser port 44 of the reservoir fills the recess102 of the medicament cup 98 such that a predetermined dose is provided.In the second position, however, the ratchet 106 prevents the cup sled100 from being moved to the delivery passageway 34, such that the recess102 of the medicament cup 98 remains aligned with the dispenser port 44of the reservoir 14 and the pressure relief port 116 of the spacer 38remains sealed by the second sealing surface 124 of the cup assembly 96.

Upon the cover 28 being fully opened such that the third cam surfaces 94engage the cam followers 78, the actuator spring 69 is allowed to movethe yokes 66,68 further towards the mouthpiece 24 to the third position.When moved to the third position, the ratchet 106 disengages, or fallsbelow the boss 110 of the cup sled 100 and allows the cup sled 100 to bemoved by the cup spring 104, such that the filled recess 102 of the cup98 is position in the venturi 36 of the delivery passageway 34 and thedispenser port 44 of the reservoir 14 is sealed by the first sealingsurface 118 of the cup assembly 96. In addition, the pressure reliefport 116 is uncovered by the indentation 126 in the side surface of thesled 100 to release pressure from the reservoir 14 and allow the bellows40 to further collapse and accommodate the movement of the yokes 66,68to the third position. The inhaler 10 is then ready for inhalation by apatient of the dose of medicament placed in the delivery passageway 34.

As shown in FIG. 16, a breath-induced air stream 4′ diverted through thedelivery passageway 34 passes through the venturi 36, entrains themedicament and carries the medicament into the deagglomerator 10′ of theinhaler 10. Two other breath-induced air streams 2′, 3′ (only one shown)enter the deagglomerator 10′ through the diametrically opposed inletports 24′, 25′ and combine with the medicament entrained air stream 150from the delivery passageway 34. The combined flows 4′ and entrained drypowder medicament then travel to the outlet port 32′ of thedeagglomerator and pass through the mouthpiece 24 for patientinhalation.

Once inhalation is completed, the mouthpiece cover 28 can be closed.When the cover 28 is closed, the trigger cams 70 force the yokes 66,68upwardly such that the first yoke 66 expands the bellows 40, and thepawl 138 of the second yoke 68 advances the indexing spool 134 of thedose counting system 16 to provide a visual indication of a dose havingbeen dispensed. In addition, the cup assembly 96 is forced back to thefirst position by the pusher bar 108 of the upwardly moving second yoke68 (see FIG. 13) such that the boss 110 of the cup sled 100 is engagedand retained by the ratchet 106 of the second yoke 68.

The medicament used in the inhaler of the present invention comprises amixture of micronised fluticasone propionate, micronised salmeterolxinafoate and a lactose carrier. Micronising may be performed by anysuitable technique known in the art, e.g., jet milling.

The medicament contains fluticasone propionate. It is preferable thatsubstantially all of the particles of fluticasone propionate are lessthan 10 μm in size. This is to ensure that the particles are effectivelyentrained in the air stream and deposited in the lower lung, which isthe site of action. Preferably, the particle size distribution of thefluticasone propionate is: d10=0.4-1.1 μm, d50=1.1-3.0 μm, d90=2.6-7.5μm and NLT95%<10 μm; more preferably d10=0.5-1.0 μm, d50=1.8-2.6 μm,d90=3.0-6.5 μm and NLT99%<10 μm; and most preferably d10=0.5-1.0 μm,d50=1.90-2.50 μm, d90=3.5-6.5 μm and NLT99%<10 μm.

The particle size of the fluticasone propionate may be measured by laserdiffraction as an aqueous dispersion, e.g., using a Malvern Mastersizer2000 instrument. In particular, the technique is wet dispersion. Theequipment is set with the following optical parameters: Refractive indexfor fluticasone propionate=1.530, Refractive index for dispersantwater=1.330, Absorption=3.0 and Obscuration=10-30%. The samplesuspension is prepared by mixing approximately 50 mg sample with 10 mlof de-ionized water containing 1% Tween® 80 in a 25 ml glass vessel. Thesuspension is stirred with a magnetic stirrer for 2 mins at moderatespeed. The Hydro 2000S dispersion unit tank is filled with about 150 mlde-ionized water. The de-ionized water is sonicated by setting theultrasonics at the level of 100% for 30 seconds and then the ultrasonicis turned back down to 0%. The pump/stirrer in the dispersion unit tankis turned to 3500 rpm and then down to zero to clear any bubbles. About0.3 ml of 1% TA-10X FG defoamer is added into the dispersion media andthe pump/stirrer is turned to 2000 rpm and then the background ismeasured. Slowly the prepared suspension samples are dropped into thedispersion unit until a stabilized initial obscuration at 10-20% isreached. The sample is continued to be stirred in the dispersion unitfor about 1 min at 2000 rpm, then the ultrasound is turned on and thelevel is set to 100%. After sonicating for 5 min with both the pump andultrasound on, the sample is measured three times. The procedure isrepeated two more times.

The delivered dose of fluticasone propionate is preferably 25-500 μg peractuation.

The medicament contains salmeterol xinafoate. It is preferable thatsubstantially all of the particles of salmeterol xinafoate are less than10 μm in size. This is to ensure that the particles are effectivelyentrained in the air stream and deposited in the lower lung, which isthe site of action. Preferably, the particle size distribution of thesalmeterol xinafoate is: d10=0.4-1.3 μm, d50=1.4-3.0 μm, d90=2.4-6.5 μmand NLT95%<10 μm; more preferably d10=0.6-1.1 μm, d50=1.75-2.65 μm,d90=2.7-5.5 μm and NLT99%<10 μm; most preferably d10=0.7-1.0 μm,d50=2.0-2.4 μm, d90=3.9-5.0 μm and NLT99%<10 μm.

The particle size of the salmeterol xinafoate may be measured using thesame methodology as described for fluticasone propionate. In particular,the technique is wet dispersion. The equipment is set with the followingoptical parameters: Refractive index for salmeterol xinafoate=1.500,Refractive index for dispersant water=1.330, Absorption=0.1 andObscuration=10-30%. The sample suspension is prepared by mixingapproximately 50 mg sample with 10 ml of de-ionized water containing 1%Tween® 80 in a 25 ml glass vessel. The suspension is stirred with amagnetic stirrer for 2 mins at moderate speed. The Hydro 2000Sdispersion unit tank is filled with about 150 ml de-ionized water. Thede-ionized water is sonicated by setting the ultrasonics at the level of100% for 30 seconds and then the ultrasonic is turned back down to 0%.The pump/stirrer in the dispersion unit tank is turned to to 3500 rpmand then down to zero to clear any bubbles. About 0.3 ml of 1% TA-10X FGdefoamer is added into the dispersion media and the pump/stirrer isturned to 2250 rpm and then the background is measured. The preparedsuspension samples are slowly dropped into the dispersion unit until astabilized initial obscuration at 15-20% is reached. The sample iscontinued to be stirred in the dispersion unit for about 1 min at 2250rpm, then the ultrasound is turned on and the level is set to 100%.After sonicating for 3 min with both the pump and ultrasound on, thesample is measured three times. The procedure is repeated two moretimes.

The delivered dose of salmeterol xinafoate (as base) is less than 50 μgper actuation, more preferably less than 40 μg per actuation, morepreferably less than 30 μg per actuation, more preferably less than 25μg per actuation and most preferably less than 15 μg per actuation,based on the amount salmeterol present (i.e. the amount is calculatedwithout including contribution to the mass of the counterion).

Particularly preferred delivered doses of fluticasone/salmeterol in μgare 500/12.5, 400/12.5, 250/12.5, 200/12.5, 100/12.5, 50/12.5 or25/12.5.

The inhaler of the present invention administers a delivered dose offluticasone/salmeterol which provides a baseline-adjusted FEV₁ in apatient of more than 150 mL within 30 minutes of receiving the dose. Thebaseline-adjusted FEV₁ preferably remains above 150 mL for at least 6hours after receiving the dose.

The delivered dose of the active agent is measured as per the USP <601>,using the following method. A vacuum pump (MSP HCP-5) is connected to aregulator (Copley TPK 2000), which is used for adjusting the requireddrop pressure P₁ in a DUSA sampling tube (Dosage Unit SamplingApparatus, Copley). The inhaler is inserted into a mouthpiece adaptor,ensuring an airtight seal. P₁ is adjusted to a pressure drop of 4.0 KPa(3.95 -4.04 KPa) for the purposes of sample testing. After actuation ofthe inhaler, the DUSA is removed and the filter paper pushed inside withthe help of a transfer pipette. Using a known amount of solvent(acetonitrile:methanol:water (40:40:20)), the mouthpiece adaptor isrinsed into the DUSA. The DUSA is shaken to dissolve fully the sample. Aportion of the sample solution is transferred into a 5 mL syringe fittedwith Acrodisc PSF 0.45 μm filter. The first few drops from the filterare discarded and the filtered solution is transferred into a UPLC vial.A standard UPLC technique is then used to determine the amount of activeagent delivered into the DUSA. The delivered doses of the inhaler arecollected at the beginning, middle and end of inhaler life on threedifferent days.

It is preferable that substantially all of the particles of lactose areless than 300 μm in size. It is preferable that the lactose carrierincludes a portion of fine material, that is, lactose particles of lessthan 10 μm in size. The fine lactose fraction may be present in anamount of 1-10 wt %, more preferably 2.5-7.5 wt %, based on the totalamount of lactose. Preferably, the particle size distribution of thelactose fraction is d10=15-50 μm, d50=80-120 μm, d90=120-200 μm,NLT99%<300 μm and 1.5-8.5%<10 μm. Most preferably, the particle sizedistribution of the lactose fraction is d10=25-40 μm, d50=87-107 μm,d90=140-180 μm, NLT99%<300 μm and 2.5-7.5%<10 μm. The lactose ispreferably α-lactose monohydrate (e.g., from DMV Fronterra Excipients).

The particle size distribution of the lactose provided herein ismeasured by laser diffraction in air, e.g., with a Sympatec HELOS/BFequipped with a RODOS dispenser and VIBRI feeder unit. In particular,lens type R5: 05/4.5 . . . 875 μm is used; The following information isset on the equipment: density=1.5500 g/cm³, shape factor=1.00,calculation mode=HRLD, forced stability=0; The following triggerconditions are set: Name=CH12, 0.2%, reference duration=10 s (single),time base=100 ms, focus prior to first measurement=Yes, normalmeasurement=standard mode, start=0.000 s, channel 12 0.2%, valid=always,stop after=5.000 s, channel 12≦0.2%, or after=60.000 s, real time,repeat measurement=0, repeat focus=No; The following disperserconditions are set: Name 1.5 bar; 85%; 2.5 mm, dispersing type=RODOS/M,injector=4 mm, with=0 cascade elements, primary pressure=1.5 bar, alwaysauto adjust before ref. meas.=No, feeder type=VIBRI, feed rate=85%, gapwidth=2.5 mm, funnel rotation=0%, cleaning time=10 s, use VIBRIControl=No, vacuum extraction type=Nilfisk, delay=5 s. An adequateamount of approximate 5 g of the sample is transferred into a weighingpaper using a clean dry stainless steel spatula, and then poured intothe funnel on the VIBRI chute. The sample is measured. The pressure ismaintained at about 1.4-1.6 bar, measurement time=1.0-10.0 seconds,C_(opt)=5-15% and vaccum≦7 mbar. The procedure is repeated two moretimes.

The inhaler described herein is provided for the treatment of asthma orCOPD.

EXAMPLES Example 1

Dry powder formulations were prepared by combining the followingingredients:

-   -   fluticasone propionate having a particle size of d10=0.5-0.9 μm,        d50=1.5-2.4 μm, d90=3.3-6.0 μm, and NLT99%<10 μm.    -   salmeterol xinafoate having a particle size of d10=0.6-1.1 μm,        d50=1.75-2.65 μm, d90=2.7-5.5 μm, and NLT99%<10 μm.    -   α-lactose monohydrate (DMV Fronterra Excipients) having a        particle size of d10=25-40 μm, d50=87-107 μm, d90=140-180 μm,        NLT99%<300 μm and 3-9%<10 μm,

Formulations were provided having delivered doses of fluticasonepropionate/salmeterol xinafoate of 100/6.25, 100/12.5, 100/25 and 100/50mcg.

Example 2

A six-period crossover, dose-ranging study was performed to evaluate theefficacy and safety of four doses of FS Spiromax® (fluticasonepropionate/salmeterol xinafoate inhalation powder) administered assingle doses compared with single doses of fluticasone propionateSpiromax® and open label Advair® Diskus® in adult and adolescentsubjects with persistent asthma.

Fluticasone propionate/salmeterol xinafoate Spiromax® was manufacturedby Teva Pharmaceuticals. The specifications were as set out inExample 1. Doses tested were fluticasone propionate/salmeterol xinafoate100/6.25, 100/12.5, 100/25, and 100/50 mcg. Advair® Diskus® wasmanufactured by GlaxoSmithKline and is a commercially available product.The label claim emitted dose of fluticasone propionate/salmeterolxinafoate of Advair® Diskus® was 100/50 mcg which is equivalent todelivered dose of 93/45 mcg.

Assessments were performed using forced expiratory volume in 1 second(FEV₁) measurements. The study included a run-in period is to completebaseline safety evaluations and to obtain baseline measures of asthmastatus, including baseline FEV₁ measurements.

It was found that the product of the present invention providedcomparable efficacy (as determined by FEV₁ measurements) despite havingan approximately four-fold lower dose of salmeterol xinafoate than thatof the commercially available product. This substantial reduction indose was surprising and suggests a synergistic relationship between thecomponents tested which could not have been predicted in advance. Theseresults were also not found during in vitro testing. The results areshown graphically in FIG. 23.

FIG. 23 compares FS Spiromax® at a delivered dose of 100/12.5 mcg (curvelabelled “100/12.5”) and Advair® at a dose of 100/50 mcg (curve labelled“100/50”). The two curves are surprisingly close given the approximatelyfour-fold lower dose of salmeterol in the product of the presentinvention.

1. A dry powder inhaler comprising: a dry powder medicament comprisingfluticasone propionate, salmeterol xinafoate and a lactose carrier;wherein, the delivered dose of salmeterol per actuation is less than 50μg; and wherein the dose provides a baseline-adjusted FEV₁ in a patientof more than 150 mL within 30 minutes of receiving the dose.
 2. Theinhaler as claimed in claim 1, wherein the baseline-adjusted FEV₁remains above 150 mL for at least 6 hours after receiving the dose. 3.The inhaler as claimed in claim 1, wherein the dose of salmeterol isless than 25 μg.
 4. The inhaler as claimed in claim 3, wherein the dosesof fluticasone/salmeterol in μg are 500/12.5, 400/12.5, 250/12.5,200/12.5, 100/12.5, 50/12.5 or 25/12.5 per actuation.
 5. The inhaler asclaimed in claim 1, wherein the particle size of the fluticasonepropionate is d10=0.4-1.1 μm, d50=11.1-3.0 μm, d90=2.6-7.5 μm andNLT95%<10 μm, measured by laser diffraction as an aqueous dispersion. 6.The inhaler as claimed in claim 1, wherein the particle size of thesalmeterol xinafoate is d10=0.4-1.3 μm, d50=1.4-3.0 μm, d90=2.4-6.5 μmand NLT95%<10 μm, measured by laser diffraction as an aqueousdispersion.
 7. The inhaler as claimed in claim 1, wherein the lactosecarrier is composed of a coarse lactose and fine lactose, wherein thefine lactose is defined by a particle size of <10 μm, measured by laserdiffraction as a dispersion in air.
 8. The inhaler as claimed in claim7, wherein the lactose contains 1-10 wt % of fine lactose.
 9. Theinhaler as claimed in claim 1, wherein the lactose particle size isd10=15-50 μm, d50=80-120 μm, d90=120-200 μm.
 10. The inhaler as claimedin claim 1, wherein the inhaler comprises a cyclone deagglomerator forbreaking up agglomerates of the dry powder.
 11. The inhaler as claimedin claim 10, wherein the deagglomerator comprises: an inner walldefining a swirl chamber extending along an axis from a first end to asecond end; a dry powder supply port in the first end of the swirlchamber for providing fluid communication between a dry powder deliverypassageway of the inhaler and the first end of the swirl chamber; atleast one inlet port in the inner wall of the swirl chamber adjacent tothe first end of the swirl chamber providing fluid communication betweena region exterior to the deagglomerator and the first end of the swirlchamber; an outlet port providing fluid communication between the secondend of the swirl chamber and a region exterior to the deagglomerator;and vanes at the first end of the swirl chamber extending at least inpart radially outwardly from the axis of the chamber, each of the vaneshaving an oblique surface facing at least in part in a directiontransverse to the axis; whereby a breath induced low pressure at theoutlet port causes air flows into the swirl chamber through the drypowder supply port and the inlet port.
 12. The inhaler as claimed inclaim 1, wherein the inhaler comprises a reservoir for containing themedicament and an arrangement for delivering a metered dose of themedicament from the reservoir.
 13. The inhaler as claimed in claim 1,wherein the inhaler comprises a delivery passageway for directing aninhalation-induced air flow through a mouthpiece, a channel extendingfrom the delivery passageway to the medicament.
 14. The inhaler asclaimed in claim 1, comprising: a sealed reservoir including adispensing port; a channel communicating with the dispensing port andincluding a pressure relief port; a conduit providing fluidcommunication between an interior of the sealed reservoir and thepressure relief port of the channel; and a cup assembly movably receivedin the channel and including, a recess adapted to receive medicamentwhen aligned with the dispensing port, a first sealing surface adaptedto seal the dispensing port when the recess is unaligned with thedispensing port, and a second sealing surface adapted to sealing thepressure relief port when the recess is aligned with the dispensing portand unseal the pressure relief port when the recess is unaligned withthe dispensing port.
 15. (canceled)
 16. A method for the treatment ofasthma or allergic rhinitis or COPD comprising administering to apatient a dry powder medicament comprising fluticasone propionate,salmeterol xinafoate and a lactose carrier; wherein, the delivered doseof salmeterol per actuation is less than 50 μg; and wherein the doseprovides a baseline-adjusted FEV₁ in a patient of more than 150 mLwithin 30 minutes of receiving the dose.
 17. The method as claimed inclaim 16, wherein the dose of salmeterol is less than 25 μg.
 18. Themethod as claimed in claim 16, wherein the dose offluticasone/salmeterol in μg is 500/12.5, 400/12.5, 250/12.5, 200/12.5,100/12.5, 50/12.5 or 25/12.5 per actuation.
 19. A method of measuring adelivered dose of active agent by an inhaler comprising: inserting theinhaler into a mouthpiece adapter; actuating the inhaler to provide adelivered dose through the mouthpiece adapter and into a dosage unitsampling apparatus; rinsing the mouthpiece adapter with a solvent andinto the dosage unit sampling apparatus; dissolving the delivered dosein the dosage unit sampling apparatus; filtering the dissolved delivereddose to provide a filtered solution; and analyzing the filtered solutionto determine the amount of the active agent in the delivered dose. 20.The method as claimed in claim 19, wherein the method is carried out atthe beginning, the middle and the end of the life of the inhaler.